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Antimicrobial Agents and Chemotherapy, February 2008, p. 491-496, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00909-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir{triangledown}

Sidonie Lambert-Niclot,1* Philippe Flandre,2 Ana Canestri,3 Gilles Peytavin,4 Christine Blanc,3 Rachid Agher,3 Cathia Soulié,1 Marc Wirden,1 Christine Katlama,3 Vincent Calvez,1 and Anne-Geneviève Marcelin1

Departments of Virology,1 INSERM U720,2 Infectious Diseases, Pitié-Salpêtrière Hospital, Paris, France,3 Department of Pharmacy, Bichat-Claude Bernard Hospital, Paris, France4

Received 11 July 2007/ Returned for modification 11 September 2007/ Accepted 9 November 2007

The objective of this study was to characterize the mutations selected by darunavir (DRV) use in protease inhibitor (PI)-experienced patients and the associated factors. We analyzed treatment failure in 54 PI-experienced human immunodeficiency virus (HIV)-infected patients on a DRV- and ritonavir-containing regimen. Viral genotyping was carried out at the baseline, at between 1 and 3 months of treatment, and at between 3 and 6 months of treatment to search for the selection of mutations conferring resistance to PIs. The median baseline HIV RNA level was 4.9 log10 copies/ml, and the median CD4 count was 87 cells/mm3. At the baseline, the median numbers of resistance mutations were as follows: 3 DRV resistance mutations, 4 major PI resistance mutations, and 10 minor PI resistance mutations. The most common mutations that emerged at rebound included V32I (44%), I54M/L (24%), L33F (25%), I84V (21%), and L89V (12%). Multivariate analysis showed that higher baseline HIV RNA levels and smaller numbers of nucleoside reverse transcriptase inhibitor simultaneously used with DRV were associated with a higher risk of DRV resistance mutation selection. By contrast, L76V, a known DRV resistance mutation, was found to decrease the risk of selection of another DRV resistance mutation. The occurrence of virological failure while a patient was on DRV was associated with the selection of mutations that increased the level of DRV resistance without affecting susceptibility to tipranavir (TPV). In these PI-treated patients who displayed treatment failure while they were on a DRV-containing regimen, we confirmed the set of emerging mutations associated with DRV failure and identified the factors associated with the selection of these mutations. TPV susceptibility does not seem to be affected by the selection of a DRV resistance mutation.

* Corresponding author. Mailing address: Department of Virology, Pitié-Salpêtrière Hospital, 83 Boulevard de l'Hôpital, Paris 75013, France. Phone: 33142177409. Fax: 33142177411. E-mail: sidonie.lambert{at}psl.aphp.fr

{triangledown} Published ahead of print on 26 November 2007.

Antimicrobial Agents and Chemotherapy, February 2008, p. 491-496, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00909-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tartaglia, A., Saracino, A., Monno, L., Tinelli, C., Angarano, G. (2009). Both a Protective and a Deleterious Role for the L76V Mutation. Antimicrob. Agents Chemother. 53: 1724-1725 [Full Text]  
  • Lambert-Niclot, S., Flandre, P., Malet, I., Canestri, A., Soulie, C., Tubiana, R., Brunet, C., Wirden, M., Katlama, C., Calvez, V., Marcelin, A.-G. (2008). Impact of gag mutations on selection of darunavir resistance mutations in HIV-1 protease. J Antimicrob Chemother 62: 905-908 [Abstract] [Full Text]  


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